Howdy, PARTNER: Gay Men and HIV Transmission

PositiveLite.com Editor Bob Leahy in Conversation With CATIE's James Wilton on What the PARTNER Study Tells Us About the Risk of HIV Transmission in Gay Men Where One Partner Is HIV-Positive but Who's Viral Load Is Undetectable

But simply because there were no HIV transmissions in the study does not mean that the risk going into the future is zero?

There is always the possibility for chance to influence research results. In general, the larger the study, the less likely that the results are due to chance. For example, if the participants in the PARTNER study had engaged in a million sex acts with no HIV transmissions, the potential role of chance would have been much smaller and the researchers could be more confident that the "true" risk is zero. On the other hand, if this analysis had only included 100 condomless sex acts, then the potential role of chance would have been much larger and the researchers would be less confident that the "true" risk is zero.

To understand the role that chance may have played in the PARTNER study, the researchers calculated upper confidence limits for their results. Confidence limits are basically a tool that researchers can use in order to take into account the potential effects of chance and produce a range of values in which they can be very confident that the "true" risk lies.

I will use the results for receptive anal sex as an example for how these confidence limits can be interpreted.

In the preliminary analysis of the PARTNER study, the upper confidence limit for the risk of HIV transmission through one act of condomless receptive anal sex when the viral load is undetectable was calculated to be 0.05% (equivalent to 1 transmission per 2000 exposures). This means that the "true" risk through one act of condomless receptive anal sex when undetectable is extremely likely to be lower than 0.05%. This is very significant because the average risk through one act of condomless receptive anal sex when the viral load is detectable is 1.4% (equivalent to 1 transmission per 71 exposures). The reduction from 1.4% to 0.05% represents about a 96% change in risk, which is a dramatic reduction and equivalent to what we saw in HPTN 052 for vaginal sex.

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While the "true" risk is more likely to be closer to zero than the upper confidence limit, the researchers could not statistically rule out the possibility that the risk is as high as 0.05%. This is concerning to some extent because 0.05% is similar to the average HIV transmission risk through one act of condomless vaginal sex when the viral load is detectable, an activity that is generally considered to be "high risk" for HIV infection in most guidelines.

It is important to point out that receptive anal sex had a relatively high upper confidence limit because, during the study, relatively few of these sex acts occurred (about 7,000 compared to over 11,000 for each of the other types of sex acts). Therefore, chance could have played a greater role in the results for receptive anal sex.

As the PARTNER study continues, and more condomless receptive anal sex acts occur, the upper confidence limit will begin to "tighten" and move closer to zero (assuming no transmissions occur). This will allow the researchers to be more confident that the "true" risk is closer to zero and not potentially as high as 0.05%. This is why the study is continuing and plans to enroll more gay men.

I know this can all be pretty confusing and difficult to interpret, but I think we can boil it down to two main conclusions. First, the analysis told us that the change in risk of HIV transmission for anal sex is equivalent to that for vaginal sex. This is great news and something we didn't know. However, the second conclusion is that the study could not rule out the possibility that receptive anal sex may still be higher risk than other types of sex when the viral load is undetectable. This is unfortunate and something we hope the full analysis will rule out.

OK, in the past, we have qualified what we've known about transmission risk by saying it could be affected by STIs, in other words the presence of STIs in either partner could increase the likelihood of transmission occurring. Does PARTNER tell us anything about whether STIs still represent a complicating factor?

We have strong evidence showing that STIs can increase the risk of HIV transmission, whether it is the HIV-negative or HIV-positive person who has the STI. Unfortunately, most of the studies looking at STIs didn't keep track of the viral load of the HIV-positive partner, so it's unclear whether this is true when the viral load is undetectable.

In the PARTNER study, 16% of the gay men and 5% of the heterosexual men and women were diagnosed with an STI at some point in the study. While it is reassuring that no HIV transmissions occurred despite the presence of STIs, it is difficult to come to a more definitive conclusion. This is because the conference presentation on the preliminary analysis didn't include much information related to STIs. For example, the presentation didn't include anything about the type of STIs, their location, their duration, whether they were treated or untreated or how many of the 44,000 condomless sex acts occurred in the presence of an STI. Hopefully the final analysis of the PARTNER study will include more information so we can better understand the potential impact of STIs on the risk of HIV transmission when undetectable.

It is also important to note that the HIV-negative and positive participants in the study received regular care every six months, which included testing and treatment for STIs. This may have helped limit the impact of STIs on HIV transmission. So, for now, I think our messaging needs to continue to state that STIs may increase the risk of HIV transmission when undetectable.

What about the semen issue? We've always made the point that virus in the semen may occur when it is not measurable in the blood, How important is that a factor now given that there were zero transmissions recorded in x number of sexual acts in PARTNER, even though it seems virtually certain that there was virus in the semen of at least some otherwise undetectable participants? Granted we don't know at what levels and what is enough to cause transmission. But surely if virus in the semen mattered as a significant risk factor we would have seen some transmissions?

We know that people who have an undetectable viral load in the blood can sometimes have detectable (although lowered) levels of the virus in their other bodily fluids, including semen, vaginal fluid and rectal fluid. However, as you point out, the implications of this phenomenon for HIV transmission are not well defined.

While some studies show that the viral load discordancy between blood and other bodily fluids is common, others suggest it is uncommon. Unfortunately, the PARTNER study didn't monitor the viral load in the genital and rectal fluids, so we don't know how common this phenomenon was among participants in the PARTNER study. This makes it difficult to come to any definitive conclusions. However, it's very likely that at least some of the participants had detectable levels in their other bodily fluids, so it is reassuring to some extent that no HIV transmissions occurred.

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